DESCRIPTION (Taken from the Applicant?s Abstract) This application proposes to produce and analyze mice that have been engineered to express attenuated alleles of cell cycle regulatory genes. It is anticipated that such alleles exist in human populations, but manifest predominantly after environmental challenge. The cell cycle regulatory genes that will be targeted are those encoding members of the Cyclin D/Cdk4, Rb, P14ink6 complex, which plays a critical role in the passage of cells through the G1 phase of the cell cycle. Initial emphasis will be given to a cyclin D1 polymorphism that is known to predispose to hereditary non-polyposis colorectal cancer (HNPCC). This project will be directed by Dr. Knudsen who is expert in the biology of Rb and the Cyclin D/Cdk4 complex. A second project, to be directed by Dr. Yolanda Sanchez, focuses on the G2 checkpoint and the cell cycle regulatory gene, Chkl. Dr. Sanchez?s expertise is in yeast genetics as well as in the mechanisms governing transit of cells through G2 and M phases. Dr. Stambrook is the principal investigator of this grant and will direct a third project that will produce mice with attenuated alleles of the Polo kinase, Plk3. This kinase, like Chkl, has G2/M regulatory function and is responsive to DNA damage. The University of Cincinnati College of Medicine has made commitments to institutional core facilities, which include a mouse Transgenic Core and a mouse knockout core. This core was established and is directed by Dr. Tom Doetschman, who plays a key role in this proposal. Other established cores include a DNA synthesis and sequencing core directed by Dr. Joanna Groden, a member of our internal advisory committee, a comparative pathology core directed by Dr. Greg Boivin, and a biostatistics core. Three new integrated cores funded, in part, by the Howard Hughes Medical Institute, by the Dean of the medical school, and by the Children?s Hospital Research Foundation, are available. These include a DNA microarray core, a proteomics core, and a bioinformatics core. This application proposes to take advantage of these core facilities and to contribute the collective expertise of the investigators in furthering the understanding of the interactions between environmental challenge and variant cell cycle genes in the genesis of disease.